Alpha-lipoic acid process



Unite z,s1'1,2ss ALPHA-mom ACID raocass Carl S. Homberger, In, Wilmington, Del, asaignor to E. I. du Pont de Nemonrs and Company, Wilmington, Del., a corporation of Delaware No Drawing. Application May 28, 1954, Serial No. 433,281

1 Claim. (Cl. 260-327) This invention relates to a process for preparing alphalipoic acid, which is a cyclic disulfide of the formula 30 0 0 (OHah-CH-OHa-OHs-SON BOIB' BO 0 C (OHsh-CH-OHr-OH;

use as an antioxidant in fats, in hair waving formulations, as an agent for complexing heavy metals in treating heavy metal poisoning, and as a food supplement to improve the diet of animals.

The isolation of iipoic acid from natural sources is not commercially practical because of the small amount to be found in nature and because of difliculties in isolation. Several routes for its synthesis by chemical means have been developed which make use of an oxidative ring closure using a dimercapto-octanoic acid as an intermediate. This oxidative ring closure is accompanied by polymer formation. When an oxidant other than iodine is used, there is a danger of forming higher oxidized products. A disadvantage to the use of iodine is its cost.

States Patent 0 2,877,235 Patented Mar. 10, 1959 "ice I have now found that a compound of Formula 1 can be prepared without an external oxidant and with a minimum of polymer formation by the alkaline treatment of a dithiocyano derivative of a fatty acid ester having the formula (2) aooccaorom-cnrcm-scn where R is a lower alkyl group containing from 1 to 6 carbon atoms.

This alkaline reaction which leads to ring closure is conducted in a relatively concentrated solution and'without regard to a balanced stoichiometry with reference to the ring closing agent.

The dithiocyanate derivative of a fatty acid ester represented by Formula 2, which is reacted with alkali to form, after acidification, lipoic acid or a homolog, can be prepared from hydroxy or halogen-substituted fatty acid esters, or esters containing both hydroxy and halogen groups, by a sequence of reactions with salts of thiocyano acid or treatment with an organo sulfonyl halide followed by treatment with a salt of thiocyanic acid. This aequence of reactions is graphically shown below.

3 a'soicll a acid acceptor 2'50 01 and writer I ROUTE A nooc-(cHm-cn-omon,

H l 1 use /a) a lusou uiiim noomgnm-cn-orn-cm ON ON ROUTE 13 BO 0 O (CHs)tOH-OHs-OH; ON OH l 8013' (DlMBCN t aoocwmn-cn-cm-cm scN ON In Routes A and B, R has the same significance as in Formula 2, R is alkyl, aryl or alkaryl, and M represents alkali metal or ammonium.

ON BOIB' HSONlG) BDOOKIHMOEOHaO 2:;

normal 3 Qcanbeiaolatedortreatedinthesameaolventivifl a 1 salt of thioeyanigt to the deelreduh z'ditllioo derivative a ester orm BOOOwmPOH-CHPCH' i l! alternative route c npri'sing steps a, c, and e is to treat the hydroxychloro compound of Formula 3 R R and M have the same si as in Route A. with a salt of thiocyanic acid to produce a hydro ry throcyano compound of Formula 4. This hydroxy thiocyano ROUTE D compound can then be treated in a solvent with an organo (13) noocwm) caom'?na sulfonyl halide in the presence of an acid acceptor. The

lial. In: solvent may be inert or a tertiary amine. The resultant thiocyanosulfonic ester of Formula 6 can then be treated HBONl (a) with a salt of thiocyanic acid tfo give utilt: de-

' f t d este Form m noocwlmrcnwmm rrvatrve of a a ty ac: r 0

Another method of preparing a compound of For- ON 15 girls 2 is illustrated by steps "ku; and l'kstartmbg with a have the same si cause as in Routes A, B ydrcxy compound for Form a 11. dou le quanan f nrhal represents a iii? of the class consisting y 05111? Ol'gano sulionyl hal de is employed with a weak of 1 1 b a d i di base to yield a double sulfomc acid of Formula 12, fol- Illustrative ol'the compounds which may be used as lowed by treatm t with a salt of thiocyamc acid.

starting materials in Routes A, B, C or 1), there may be so The conversion of the d1halo compound or Formula 13 mentioned the following: to h i h wy n compound involves treatment with a e salt of thiocyanic acid. g g g g zmg ggi fi Among the preferred organo sulfonyl halides are a g i t methane sulfonyl chloride and toluene sulionyl chloride.

Other sulfonyl halides may, however, be but they are generally more expensive. Methane sulfonyl chloride is pgtitlrticularly preferred of its low mol Wei t.

Anyofavarietyotcommaybsusedasthe acid acceptor including tertiary aminm or weakly basic inorganic salts such as, for ce, sodi carbonate, so-

dium bicarbonate or calcium carte. dine triethylamine are preferred acid accep bemuse they also function as solvents. I! i n a the tertiary may be diluted with an orc solvent as benzene or etherto n; t. t, I

acid which are cm- Propyl 8-chloro-6-hydroxyocte t-Butyl 8-chloro-6-hydroxyoctanoate n-Butyl S-chloro-fi-hydroxyoctanoate Sec-butyl 8-chloro-6-hydroxyoctanoatc Iso-amyl 8-chloro-6-hydroxyoctanoate n-Amyl 8-chloro-6-hydroxyoate Hexyl 8-chloro-6-hydroxyoctanoate Methyl 6,8-dibromooctanoate Ethyl 6,8-dichlorooctanoate Methyl 6,8-dihydroxyoctanoate Ethyl 6,8-dihydroxyoctanoate Methyl 6-chloro-8-hydroxyoctanoate t-Butyl iu 11:. Ethyl 6-bromo-8chlorooctanoate Ethyl B-bromo-G-chlorooctanoate Ethyl 6-chloro-8-iodooctanoate The preferred salts of i -1 ployed in the p of this inventim are i M or sodium thiocyanate. 1 1- n thiocyanate or other metal thiocyanates such as, for i :r m calcium, may be v used but the rate of reaction is slower when they are used Ethyl in contrast to when alkali I tea are em- Compcunda of Formula 3, and of Formula '13 where ployed. e halogen is chlorine, are fully described in U. 8. Patent Although the t... of the 2,792,406. In brief, these compounds can be prepared halo group with the metal m from the Friedel-Crafts addition of an olefin to an acid at a high temperature at which the salt is molten, it is chloride derived from a half acid ester. preferred to conduct the reaction at more moderate tem- Broadly speaking, compounds of Formulae 3, 7, ll and peratures in the cc of an inert solvmt such as, for 13, that is, the starting materials for Routes A, B, C and instance, benzene. In order to incr the solubility of D, can be prepared in accordance with the synthesis outthe thiocyanate salt dimethyl fo lined hereafter, wherein X is a halogen having an ac to a more soluble complex wi number above 9. converm'on ct i of n ula 2 to so aoootcnotooon i nooowmicox axon! our NoBE; BOOCWEM HOEsOHc 0- BOOOMHsMOOOHsO n aoootomncoomomon olsox, Nan

BOOO(OHs)tOH(OH)OHsOEs0E m m aooctcmhomm-omomon Referring to Routes A and B, it will be noted that alpha-lipoic acid or a homolog erect -z; treatin step b or "i," the hydroxychloro compound is mined ment is efiected in solution. A convenient reaction with an organosulfonyl chloride, preferably in a solvent. medium is an alcohol such as, for instance, ethanol. An acid acceptor, such as for instance, a tertiary amine Anhydrous alcohol is not essential. In fact, in some inor a weak organic base, maybe added to remove-the by- I stances, better yields are obtained when some water is product mineral acid. An excess amine may be used as present. In order that the reaction may be completed a solvent or an inert diluent may be used. in a reasonable e a strong such as sodium or The intermediate halosulfonic ester of Formulae 5 and i5 potassium hydroxide is preferably used. For this e menses reason, the temperature preferred is about the boiling point of the solvent. The use of a strong base also brings about a cleavage of the ester group so that the free acid may be isolated after acidification. An oxygenfree atmosphere is preferred. This reduces the oxidation of lipoic acid which may take place under alkaline conditions. As regards the isolation of the resulting lipoic acid, or homolog thereof, convenient practices used in the isolation of a fatty acid may be followed.

Considering in more detail the formation of the organosulfonyl ester, it should be pointed out that a preferred method is to add the sulfonyl halide to a solution comprising a hydroxy compound of Formula 3, 4, 7, 8, or 11 and a tertiary amine. The hydroxy compound may be added to a mixture of sulfonyl halide and tertiary amine. The addition of the tertiary amine to a mixture of the hydroxyl compound and sulfonyl halide is less desirable. When a sulfonyl 'halide and the hydroxyl compound are mixed, a dimcultly controlled spontaneous reaction may occur. This leads to byproducts.

Ordinarily, the hydroxyl compound and the sulfonyl halide are employed in about equimolar amounts. The tertiary amine is used in from 10 to 30% excess in the event an inert solvent is used. therwise,'the amine is used in larger amounts suflicient to dissolve. all reactants. The hydroxyl compounds, sulfonyl halide and tertiary amine should be as free from water as possible because the sulfonyl halide is destroyed in amounts corresponding to the amount of water present. For this reason, an atmosphere of dry nitrogen is often used to prevent reaction with atmospheric moisture.

The temperature range for satisfactory reaction of the sulfonyl halide with the hydroxy substituted compound is in the range of from to 20 C. Some decrease in yield is noted at temperatures above 20 C. Above 40', the yield drops substantially. Below 5 C. the reaction proceeds slowly.

The sulfonyl halide-hydroxy compound reaction as judged by the precipitation of the by-product amine salt proceeds to near completion within two hours. No decrease has been observed when the reaction time has been increased to about 18 hours.

Inasmuch as the reaction between the sulfonyl halide and the hydroxy substituted fatty acid ester proceeds with the formation of a precipitated salt, stirring is preferable to prevent unchanged reactants from being occluded to the precipitate. Stirring helps to maintain a homogeneous state in the liquid phase.

As regards the isolation of the organosulfonyl ester of Formulae 5, 6, 9, 10, 12 the reaction mixture is filtered after the reaction is completed to remove the precipitated salt. Alternatively, the by-product salt can be removed by washing with cold water. Evaporation in vacuo of the solvent at a pressure less than 40 mm. mercury and a temperature of less than 50 C. is practised to obtain the sulfonyl ester as a crude oil. However, the sulfonyl ester can be used in solution without the necessity of evaporation if the salt is removed. When an amine is used as an acceptor, the by-product amine salt can be removed by decomposition with sodium bicarbonate.

The replacement of the organo halide by a thiocyanate salt in the processes of my invention involves mixing the substituted organic ester with a thiocyanate salt, preferably in the presence of a solvent, bringing the reactants to reaction temperature. Without the presence of a solvent the replacement of the halogen by the isocyanate group requires a temperature in the range of from 170 v to 200 C. This temperature is necessary to melt the alkali thiocyanate. However, in the presence of an ameliorating solvent such as dimethylformamide, a temperature of from 80 to 160 C. is practical. At lower temperatures the reaction takes a longer time and at higher temperatures the product may be discolored.

Generally speaking, about equimolar amounts of the 6 substituted organic ester and thiocyanate salt are used. A slight improvement in yield is often realized in the presence of an excess of thiocyanate salt.

The replacement of the negative organohalide group by a thiocyanate may be conducted in the fused state. It is preferred, however, to use an inert solvent in which the inorganic as well as the organic components are soluble. Dimethylformamide is a preferred solvent because of the ease with which it dissolves the inorganic salt. However, other solvents such as, for instance, alcohols, ketones and esters, may be used. The presence of traces of water seems to have no effect upon the reaction.

The reactants, that is, the organohalide and metal thiocyanate, must be brought in good contact with each other in order for the reaction to be complete. Intimate mixing is essential.

Since isolation of the sulfonyl ester in a pure state is not essential for the purposes of my invention the ester may merely be washed with water to free it from the by-product salt. No further purification is required.

The replacement of the sulfonyl ester by thiocyanate salt is effected by mixing and heating the reactants until a reaction ensues. Ordinarily, the sulfonyl ester and the thiocyanate salt are used in about equimolar amounts. A slight increase in yield is sometimes obtained when about a 5% excess of the thiocyanate salt is utilized.

Since sulfonyl esters are sensitive to water in the presence of heat, the reactants should be as anhydrous as possible. However, rigorously anhydrous conditions are not critical. 1

Although the replacement of the sulfonyl ester may be accomplished in fused thiocyanate salt, it is preferred to bring about the reaction at a lower temperature in the presence of a solvent, preferably an inert organic solvent such as benzene. A preferred solvent is dimethyl formamide which forms a more soluble complex.

When the replacement of the sulfonyl esters of Formulae 5, 6, 9, 10 and 12 by thiocyanate salt is conducted in solvent any temperature between the freezing point of the solution and the boiling point may be used. In order to reduce the reaction time the preferred temperature is from about to C. When the reactants are heated in a solvent at 80 to 120' C., the time of the reaction is short. About one hour is sufiicient to insure completion of reaction.

When the reaction, that is, step d, e, h, i, l, or m, is conducted in benzene and dimethyl formamide, a formation of a gel is frequently observed. Vigorous stirring is therefore required to insure an intimate mixing of the reactants. Because a compound of Formula 2 may be used in an impure state, in the processes of the present invention, a water wash is suflicient to remove the byproduct salt.

In carrying out ring closure step of the processes of my invention, the dithiocyanate organo-ester is mixed with an alkaline solution and the mixture maintained at a temperature of from 0 to C. To decrease reaction time the mixtureis preferably kept at a temperature near that of reflux, that is, 50 to 100' C. Temperatures 30 -about 100 C. are not preferred since pressure is then required. The ring closure is effected in about 4 hours or less.

The dithiocyanate can be added to the alkali solution or the alkali can be added to a solution of the dithiocyanate. One mol of the dithiocyanate organo ester requires a minimum of three molar parts of alkali. An excess up to as much as ten parts of alkali may be used to speed the reaction to completion. The presence of water is desirable because under completely anhydrous conditions the formation of a cyclic disulfide is complicated by the formation of other products.

It is preferred to use a solvent in which both the thio; cyanate compound and alkali are soluble. Such solvents include alcohol and alcohol-water mixtures. Water alone may be used and the dithiocyanate goes into solution as to C.

' chlorie acid to a pli of 1.0-2.0. The acidified ture is mainly to assist in een heat transfer and to promote 4 even boiling.

After completion of the ring closure, the alkaline solution is madcacid with a mineral acid such as, for instance, hydrochloric acid or sulfuric acid. At this w by-product inorganic salt usually separates and can be removed by filtration. The filtrate containing lipoic acid is reduced in volume by evaporation in vacuo. The

majority of the alcohol present is thus removed from the system. The resulting mixture comprising product salts and water is extracted with a solvent to dissolve and remove lipoic acid or an analog thereof. Any of a wide variety of solvents may be used including benzene, toluene, ether and the like. The li acid, thereof, is recovered from the solvent by distillation. It is recrystallized from a solvent such as for instance petroleum ether, hexane or cyclohexane. when water alone is used as a solvent, only acidification and ction are used to obtain crude lipoic acid.

The intermediate hydroxy chloro compounds of Formulae 3 and 7 are known to be herbicides while the intermediate hydroxy thiocyano and dithiocyano compounds of Formulae 2, 4 and B are cides and are against such pests as weevils, aphids, and mites." s: compounds of Formulae 2, 4, and 8 are also active as herbicides.

- In order to better understand the invention, reference should be had to the following illustrative examples:

Example I PREPARATION OF dl-ALPHA-LIPOIC ACID Two hundred and seventy-two parts by weight of monomethyl adipate, 3500 parts of dry tetrachloroethane and 236 parts of thionyl chloride are heated slowly until reflux temperature is reached. This requires about 45 minutes. The mixture is heated at reflux temperature for an additional half-hour. Hydrogen chloride and sulfur dioxide are evolved during the reflux period. A still head is placed on the flask in place of a condenser and 100 parts of distillate are collected. The acid chloride in the flask is then cooled to -20.

To the cooled reaction mixture 453 parts of anhydrous aluminum chloride are addcdover a period of twenty minutes. Thru a tube leading to below the surface of the solvent, there is passed a rapid stream of ethylene for a period of two hours while the temperature of the reaction mixture is maintained at :5 C.

At the end of this period, the reaction mixture is poured into a rapidly stirred mixture of 2,000 parts of finely crushed ice and 250 parts of concentrated hydrochloric acid. The mixture is stirred for a period of ten minutes. The lower phase is separated from thewater and washed with two portions of water and two portions 6f 5% sodium bicarbonate solution. The time required for the decomposition and washing is about one hour.

The solution thus obtained and consisting essentially of methyl 8-chloro-6-oate, whose formula is ture of 50 C. for a period of one-half hour to decompose the excess sodium borohydride. The mixture is cooled with concentrated hydrowed wi portions of water, each portion consig of 100 parts, and one portion of dilute sodium bicarbonate solution. The product, methyl 8-chloro-6- hydroxyoctanoate, is isolated by distillation following the evaporation of the solvent in vacuo. The bo point of methyl 8-chloro-6-hydroxyoctanoate is 131-135" C. at 0.1-0.2 mercury. The index of refraction using sodium 13" light is l.4620-1.4660 at 25 C.

A mixture consisting of 104 parts of methyl 8-chloro- 6-hydroxyoate prepared as described above, 48 parts of thiocyanate and 200 parts of dry dimethyl formamide (drim by distillation) is stirred and heated. on the temperature of the mixture reaches about 100 C., the salt goes into solution. At the temperature of 140-150 C. a precipitate begins to form.

The precipitated salt can be removed by filtration. The majority of the solvent is removed in vacuo at 20 mm. Hg and up to 100 C. The crude oil is taken up in 200 parts of tetrschloroethane and washed with five 200 ml. portions of water. The addition of ferric chloride to a filtered portion of the wash water produces only a slight red color. The solvent is removed in vacuo. The index of refraction of methyl 6-hydroxy-8-thiocyanooctanoate pyridine and 100 parts of dry benzene in a vessel cooled to 15 C., and adding to the vessel 29 parts of metham sulfonyl chloride over a period of 15 minutes. The

. temperature of the reaction mixture is allowed to rise to 25 C. The mixture is stirred for a period of two hours. this period the solution becomes filled with fine crystals of pyridine hydrochloride, which are removed by filtration. Th'm filtration is effected with care being taken to exclude or.

To a mixture comprising 300 parts of dry dimethyl formamide and 48 parts of potassium thiocyanate and heated to a temperature of about C., there is added the methyl G-hydroxy-B-thiopyanooctanoate methane sulfonic acid, from the previous step, at such a rate that the temperature of the reaction mixture does not drop below 130 C. During this addition, benzene is distilled out of the mixture.

After the addition is completed, the heating is continued for an additional ten minutes. The reaction mixture is then cooled to about 110' C. and 500 parts of dry tetrachloroethane is added. After the mixture is cooled to l5-20 C. it is filtered with the aid of Celite. The filtrate is washed with from two to five portions of water, that is, until the ferric chloride test for thiocyanatc is negadve. Occasionally it may be necessary to clarify the two phase suspension of the first wash by passing through Celite wetted with tetrachloroethane. The solvent is removed in vacuo.

The resulting dark oil consisting essentially of methyl 6,8-dithiocyanooctanoate is dissolved in 1500 parts of denatured alcohol. To the resulting solution there is 1 added a mixture of 55 parts of potassium hydroxide. The mixture is heated under reflux for a period of from 1 to 2 hours. The mixture is then cooled to 20 C. and made acid with concentrated hydrochloric acid to pH 1.0-2.0. The salts which precipitate can be removed by filtration. The solvent is removed in vacuo. The residue is extracted with benzene. The water layer isagain extracted with a small portion of benzene. The combined benzene extracts are dried over sodium sulfate and evaporated in vacuo. The crude lipoic acid weighing 30 parts is purifled by distillation in high vacuum using a simple short path still heated by an oil bath at a temperature of 200-230 C. The crude material boils at -195 C. at0. 5 mm. mercury. Upon cooling and seeding the crude lipoic acid, crystallization occurs, M. F. 54-56 C. The

qv u

distilled lipoic acid can be further purified by dissolving in a minimum of cyclohexane at 50' C. and pouring into volumes (based upon the volume of cyclohexane) of low boiling petroleum ether. The purified dl-lipoic acid crystallizes in the cold alter seeding to give material melting at 58 to 59 C.

Analysis.Calcd. for C,H O,S,: C, 46.57; H, 6.84; S. 31.08. Found: C, 47.61, 47.30; H, 7.07, 6.94; S, 29.92.

Example 2 Nine hundred parts by weight of monoethyl adipate-is dissolved in 6382 parts by weight of tetrachloroethane. To this mixture there is added 700 parts of thionyl chloride. The mixture is stirred and heated slowlyso that at the end of one hour reflux temperature is reached. The mixture is maintained at reflux for a periodot one-half hour. 200 parts by weight of tetrachloroethane is removed by distillation.

This reaction mixture consisting essentially of carbcthoxyvalerie acid chloride is, cooled by means of a ice bath to a temperature of 7" C.

To the cooled acid chloride there is added quickly 1350 parts of anhydrous aluminum chloride. An excess of ethylene is then passed into the solution for a period of three hours at a rate of about A 'part per minute. The temperature of the reaction vessel is maintained in the range of to C. At the end of this period, the reaction mixture is poured into 6000 parts of ice and 850 parts of concentrated hydrochloric acid. The resulting mixture is stirred for a period of ten minutes and then the aqueous layer is removed by means of a siphon. The solvent layer is washed with three 3000 part portions of cold water and two portions of 5% sodium bicarbonate solution. The washed organic solution consists essentially of the ethyl ester of 8-chloro-6-ketooctanoic' acid.

The ethyl ester is cooled to a temperature of about 8' C. A slurry of 54 parts oi sodium borohydride in 1500 parts of ethanol is added to the ester over a period of about one hour. During this addition the temperature of the mixture is maintained in the range of 5-l5 C. After the mixture is stirred for a period of two hours at a temperature of l5--25 C., 100 parts of concentrated hydrochloric acid is added. The resulting mixture is filtered to remove the solid by-product salts and then washed with water and dilute sodium bicarbonate. After removal of the solvent in vacuo, the product, ethyl 8- chloro-6-hydroxyoctanoate is distilled. It boils at 160-175 C. at a pressure of 0.1 to 0.2 mm. mercury. Its index of refraction at 25 C. is 1.4590i0.0010.

A mixture consisting of 350 parts of potassium thiocyanate, 1500 parts of dimethyl formamide, and 678 parts of 8-chloro-6-hydroxyoctanoate acid ethyl ester obtained as above described'is stirred and heated to a temperature of 120130 C. for a period of one hour. Dur ing this treatment the formation of a precipitate is noted. The reaction mixture is cooled and poured in the water. An oily organic product is collected with the aid of 500 parts of benzene. The organic layer is washed with successive portions of water until a portion of the wash water gives only a slight positive test for thiocyanate ion by the ferric chloride reagent. The benzene solution is then dried over anhydrous magnesium sulfate. While it is not essential for the preparation of lipoic acid, the product,

ethyl 6-hydroxy-S-thiocyanooctanoate, can be isolated by removing the benzene in vacuo and distilling the product at 200-205' C. at 1 mm. mercury pressure. Its index of refraction at 25 C. is 1.4860:0.00l0.

A dry reaction vessel which has provision for the exclusion of atmospheric moisture is charged with 1627 parts of a benzene solution containing about 660 parts of ethyl 6-hydroxy-8-thiocyanooctanoate and 280 parts of dry pyridine. The mixture is stirred and cooled to a temperature of 7' C. 342 parts of methane sulfonyl chloride is added to the cooled mixture over a ten minute ture is stirred, heated and maintained at reflux for a two 1 hour period. During the heating a gel forms. The reaction mixture is cooled to room temperature, washed with four portions of water and dried over magnesium sulfate. Evaporation of the solvent in vacuo gives a dark oil which has an index of refraction of about 1.5060. This oil consisting mainly of ethyl 6,8-dithiocyanooctanoate can be purified by dissolving it in an equal weight of henzene and passing the benzene solution over a column of decolorizing charcoal. The resulting material has an index of refraction of 1.5081.

Two hundred and thirty parts of the crude ethyl, 6,8- dithiocyanooctanoate is dissolved in 500 parts of alcohol. This alcoholic solution is added to a mixture comprising 358 parts of potassium hydroxide, 1000 parts of water and 2500 parts of alcohol. The resulting mixture is heated for a period of six hours at reflux temperature. It is then cooled to a temperature of 15' C. and made acid by the addition of concentrated hydrochloric acid. The precipitated salts are removed by filtration; the solvent is removed in vacuo using the heat of a steam bath.

The resulting mixture of oil, salts, and water is extracted with benzene. The benzene extract is washed with water once and then dried over anhydrous magnesium-sulfate. The benzene is evaporated in vacuo to give the desired product, alpha-lipoic acid, in crude form. The crude product is distilled at 180-200 C. at 0.5 to 1.0 mm. of mercury, and crystallizes in the distillation receiver. Alpha-lipoic acid may be recrystallized. from '15 to 20 times its weight of methyl cyclohexane to giv compound melting at 58-60 C.

Example 3 To a cooled mixture comprising parts of methyl 8- chloro-6-hydroxyoctanoate, prepared as in Example 1, and parts of dry pyridine, there is added 50 parts of methane sulfonyl chloride at a temperature of 10' C. over a five minute period. After the mixture is stirred for one-half hour in the .cold and an additional half-hour at room temperature, 100 parts of anhydrous ether is added to precipitate the by-product pyridine salt. This salt is removed by filtration.

After removal of the pyridine in vacuo the oily product is combined with 80 parts of potassium thiocyanate and heated to 200 C. for a period of 15 minutes. The reaction mixture is cooled and then treated with 100 parts of alcohol to break up the mass and subsequently with water to dissolve the salt and form an oily layer.

The oily layer is collected with 500 parts of tetrachloroethane. The tetrachloroethane solution is then washed with successive portions of water, dilute sodium bicarbonate solution, dilute hydrochloric acid and water. During the wash it is preferable to clarify the two phase system by filtration thru Celite." The oil consistingmainly of crude methyl 6,8-dithiocyanooctanoate and solvent is dried over magnesium sulfate and solvent is removed in vacuo.

Fifty-six parts of crude methyl 6,8-dithiocyanooctanoate is dissolved in 600 parts of alcohol and the alcoholic solution is treated with 56 parts of potassium hydroxide dissolved in 100 parts of water at reflux temperature for a period. of one and one-half hours. A major portion of the solvent is removed in vacuo to leave about 200 parts period. The mixture is stirred in the cold for a period II of crude reaction mixture. Thismixture isdiluted with an equal volume of water and washed with ethyl acetate. dithiocyano compound at least Smolar parts of base being The aqueous solution is then acidified with concentrated available'in the reaction system initially, and maintainhydrochloric acid and extracted twice with ethyl acetate. ing the temperature of the reaction mixture from to 150 The ethyl acetate solution of alpha-lipoic acid is washed C. for a period of up to about 6 hours, whereupon ring with water and dried over sodium sulfate. After removal closure is effected.

of the solvent in vacuo, the dl-alpha lipoic acid is purified by distillation. Cited in the file of thil patent for preparing a compound of the formula I ED STATES PATENTS CH 2,077,478 Hollander et al Apr. 20, 1937 Q E 2,077,479 Hollander et a1 Apr. 20, 1937 C a :)4 2,194,517 Bousquet Mar. 26, 1940 2,535,706 Stevens et al. Dec. 26, 1950 which comprises mixing in'a hydroxylic solvent a dithio- 265890o Stevens et a1 1953 cyano compound of the formula 0 REFERENCES Hagelberg: Berichte 23, 1083 and 1084 (1890) (Beil- I ON ON stein, vol. 19, 1 and 28 (1934)). where R is lower alkyl with a base of the formula Kelly: Chem- 1935 1072'84 29:7272). MOH Suter: Org. Chem. ofSulfur (1944), pages 507 and where M is selected from the class consisting of an alkali metal and ammonium radicals, for each molar part of said UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,877,235 March 10, 1959 Carl S. Hornberger, Jr.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read. as corrected below.

Column 2, for the reactant of step (a) in Route A 'shown beneath Formula 3, reading MSG; read W) column 4, line 16, for compound for read compound of; line 68, for thereof alkaline read -thereof by a1ka11ne.

Signed and sealed this 18th day of August 1959.

Attest: KARL H. AXLINE, ROBERT C. WATSON, Attesti'ng Ofice'r. mz'ssi ner of Patents. 

